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Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients: a systematic review

Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular... Acta Neurochir (2017) 159:1013–1021 DOI 10.1007/s00701-017-3164-6 REVIEW ARTICLE - BRAIN TUMORS Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients: a systematic review 1 1,2,3 4 2,5 Oscar Persson & Jiri Bartek Jr. & Netanel Ben Shalom & Theresa Wangerid & 6,7,8 1,2 Asgeir Store Jakola & Petter Förander Received: 20 November 2016 /Accepted: 27 March 2017 /Published online: 13 April 2017 The Author(s) 2017. This article is an open access publication Abstract Publications from 1995 through 2014 with a minimum of 50 Objective Repeated controlled studies have revealed that ste- adult (>18 years) patients with unilateral VS, followed for a reotactic radiosurgery is better than microsurgery for patients median of >5 years, were eligible for inclusion. After screen- with vestibular schwannoma (VS) <3 cm in need of interven- ing titles and abstracts of the 1094 identified articles and sys- tion. In this systematic review we aimed to compare results tematically reviewing 98 of these articles, 19 were included. from single-fraction stereotactic radiosurgery (SRS) to fraction- Intervention Patients with unilateral VS treated with radiosur- ated stereotactic radiotherapy (FSRT) for patients with VS. gery were compared to patients treated with fractionated ste- Data sources and eligibility criteria We systematically reotactic radiotherapy. searched MEDLINE, Web of Science, Embase and Results No randomized controlled trial (RCT) was identified. Cochrane and screened relevant articles for references. None of the identified controlled studies comparing SRS with FSRT were eligible according to the inclusion criteria. Nineteen case series on SRS (n = 17) and FSRT (n =2)were included in the systematic review. Loss of tumor control ne- Electronic supplementary material The online version of this article cessitating a new VS-targeted intervention was found in an (doi:10.1007/s00701-017-3164-6) contains supplementary material, average of 5.0% of the patients treated with SRS and in which is available to authorized users. 4.8% treated with FSRT. Mean deterioration ratio for patients * Oscar Persson with serviceable hearing before treatment was 49% for SRS oscar.persson@sll.se and 45% for FSRT, respectively. The risk for facial nerve deterioration was 3.6% for SRS and 11.2% for FSRT and for 1 trigeminal nerve deterioration 6.0% for SRS and 8.4% for Department of Neurosurgery R03:02, Karolinska University FSRT. Since these results were obtained from case series, a Hospital, 171 76 Stockholm, Sweden 2 regular meta-analysis was not attempted. Department of Clinical Neuroscience, Karolinska Institutet, Conclusion SRS and FSRT are both noninvasive treatment Stockholm, Sweden 3 alternatives for patients with VS with low rates of treatment Department of Neurosurgery, Copenhagen University Hospital failure in need of rescue therapy. In this selection of patients, Rigshospitalet, Copenhagen, Denmark 4 the progression-free survival rates were on the order of 92– Department of Neurosurgery, Rabin Medical Center, Petah 100% for both treatment options. There is a lack of high- Tikva, Israel quality studies comparing radiation therapy alternatives for pa- Department of Neurology, St; Göran Hospital, Stockholm, Sweden tients with VS. Finally, 19 articles reported long-term tumor Department of Neurosurgery, St. Olavs Hospital, control after SRS, while only 2 articles reported long-term 7006 Trondheim, Norway FSRT results, making effect estimates more uncertain for FSRT. Department of Neurosurgery, Sahlgrenska University Hospital, Blå Stråket 5, vån 3, 41345 Göteborg, Sweden 8 Keywords Vestibular schwannoma Stereotactic Department of Clinical Neuroscience, Institute of Neuroscience and . . radiosurgery Fractionated stereotactic radiotherapy Gamma Physiology, Sahlgrenska Academy, Box 430, 40530 Göteborg, Sweden Knife LINAC 1014 Acta Neurochir (2017) 159:1013–1021 Introduction of the cell cycle [41]. On the contrary, SRS relies on a single high radiation dose, potentially affecting tumor cells also in Vestibular schwannomas (VSs) are benign intracranial tumors the non-dividing phase. Physical properties of Gamma Knife arising from the Schwann cells of the eight cranial nerve. The SRS allow a steep radiation gradient on the tumor margin, incidence has been reported to be approximately 2 in 100,000 which is important for keeping the dose to adjacent structures [21, 27, 31, 49]. Although benign, these tumors have the abil- low. While it is known that some tumors resistant to fraction- ity to grow and can cause significant symptoms due to com- ated radiotherapy may responds to radiosurgery, the precise pression of the cerebellum or brain stem or impairment of the differences of the radiobiological properties of the two modal- vestibulocochlear nerve function. Once the VS is discovered, ities are to some extent still an issue of discussion [25]. With symptoms like unilateral sensorineural hearing loss, vertigo the evolution of hypfractionated regimes a continuum has also and tinnitus can usually be traced back several years [37]. emerged between radiotherapy and radiosurgery, and some- Three different management strategies are commonly ap- times the distinction might be unclear. The most widely ac- plied after a diagnosis of VS. Conservative management in- cepted definition of what constitutes radiosurgery seems to be cluding regular scheduled magnetic resonance imaging (MRI) that of the AANS/CNS, defining radiosurgery as a maximum and audiometry is frequently used for small asymptomatic of five treatment sessions (however typically performed in a tumors. If the VS show signs of growth, or in case of neuro- single session) [4]. logical deterioration, treatment with microsurgery (MS) or A stereotactic frame is always used for Gamma Knife SRS, radiosurgery is considered. MS is the method of choice for which further enhances the precision of the delivered radia- large tumors with radiological or neurological signs of tion, and no margin is needed to compensate for movement of brainstem compression. Nowadays, MS can be performed the head [54]. However, this set-up may be perceived as more with low mortality, but it is still associated with a significant cumbersome and invasive. There is no consensus in the liter- risk of neurological sequelae such as hearing loss and facial ature on the definition of Bstereotactic^ fractionated radiother- nerve palsy [3, 5, 7, 8]. Single-dose stereotactic radiosurgery apy. However, all reports concerning FSRT subsequently in- (SRS) and fractionated stereotactic radiotherapy (FSRT) cluded in this review utilized LINAC-based systems using aiming to arrest tumor growth are the most commonly used either face masks or relocatable frames for fixation, and all noninvasive alternatives. In case series of patients suitable for used this terminology, which is why this has also been adopted radiosurgery/radiotherapy, the progression-free survival rates for this review. are comparable to those of case series of microsurgical resec- Since there is a lack of high evidence studies comparing the tion of VS [14, 16, 30, 53]. Further, controlled studies and different radiation modalities, local treatment policies and subsequent systematic reviews support the use of radiosurgery availability have determined the choice of irradiation modali- ty. In the present systematic review, we aim to study the ef- in VS patients eligible for both surgery and radiosurgery [23, 36, 38, 42, 43, 46]. Additionally, SRS and FSRTentail a lower fectiveness and safety of SRS compared to FSRT for the treat- incidence of side effects such as facial nerve palsy and hearing ment of unilateral VS. deterioration [9, 47]. In a recent Cochrane review [35]of controlled randomized trials, the authors concluded that there was insufficient evidence to recommend either surgical or radiation therapy in the treatment of VS. However, six pro- Methods spective intervention studies comparing MS to SRS all con- cluded that SRS demonstrates similar effectiveness in terms of The study was carried out based on the recommendations progression-free survival and that SRS demonstrates a signif- outlined in the Cochrane Handbook for Systematic Reviews icantly lower risk of neurological deteriorations such as facial of Interventions [20]. The review protocol was conducted ac- nerve palsies [23, 36, 38, 42, 43, 46]. Results of these studies cording to the PRISMA statement [34] and registered in were analyzed in a systematic review comparing Gamma PROSPERO International Prospective Register of Knife radiosurgery with microsurgical resection in VS eligible Systematic Reviews (registration no. CRD 42015029505). for both treatments and demonstrated better outcome after Five databases—EMBASE, MEDLINE, Web of Science, Gamma Knife radiosurgery [40, 55]. clinicaltrials.gov and the Cochrane library—were There are some different advantages/disadvantages related systematically searched for records concerning SRS and/or to the radiation techniques in SRS and FSRT. Linear acceler- FSRT for the treatment of VS published between January ator (LINAC)-based systems for FSRTare more available, and 1995 and December 2014. The systematic search was execut- due to the low fractionation dose, larger tumors can be treated. ed with Medical Subject Headings (MeSH) terms if available The theoretical rationale for dividing the prescribed total dose or as free text. The searches were performed from January 28– into 25–30 fractions is mainly to increase the chance of February 2 2015. The specific search criteria are available in targeting the tumor cells in the most radiation-sensitive phase Supplementary Table S1. Acta Neurochir (2017) 159:1013–1021 1015 An initial review of eligibility and relevance was per- Secondary end points formed based on abstracts for all records by the senior author (PF). In the second round all remaining records were review Secondary end points were: frequency of death due to tumor according to a Systematic Review Form (SRF) by two authors progression; frequency of VS patients with functional hearing independently (PF and OP, or JB and NBS). Reference lists of [Gardner Roberson (GR) class 1 and 2] deteriorating to non- the reviewed papers were crosschecked for further publica- serviceable hearing (GR class 3–5); frequency of loss of tumor tions of relevance. Statistical calculations were performed control as defined by the authors; frequency of patients with using the MedCalc tool (www.medcalc.org/calc). deterioration of facial nerve function after treatment; frequen- End points were dichotomous and are presented as frequen- cy of patients with deterioration of trigeminal nerve function cies and odds ratios (OR) with 95% confidence intervals (CI). after treatment. Regular meta-analyses were not attempted for uncontrolled case series. Results were instead reported as summarized fre- quencies for the individual end points without considering Results heterogeneity between studies. Literature search Inclusion and exclusion criteria The initial literature search yielded 1094 records after dupli- cate results had been eliminated (Fig. 1 and Supplementary Studies on adults (≥18 years) including patients with a minimal Table S1). The initial review could discard 997 records as not median (if the median was not reported, mean was used) relevant to the topic or as inadequate regarding cohort size or follow-up of 5 years, with unilateral VS (diagnosed with histo- follow-up time, and after reference cross-check 98 records pathology or typical MR appearance) published in the period were reviewed according to a systematic review protocol. 1995–2014 and treated with either SRS or FSRTwere included. After the second review round a final 19 records were found Included studies were categorized according to the follow- to fulfill all inclusion criteria [2, 6, 10, 15, 17, 19, 22, 24, 28, ing: S1, randomized controlled trials (RCTs), quasi-RCTs of 29, 33, 36, 39, 44, 48, 50, 52, 53, 56]. No randomized studies any sample size; S2, quantitative comparative study designs (S1) were identified on the subject. A number of non- not being prospective randomized studies, but including co- randomized quantitative comparative studies (S2) were found; hort studies and case control studies with ≥50 patients in total however, none of them fulfilled all criteria regarding follow- with a median follow-up time of >5 years; S3, case series with up time and/or defining the primary outcome parameter. ≥50 patients and a median follow-up time of >5 years. Papers concerning patient cohorts treated with SRS or FSRT Tumor control for novel tumors or regrowth of a previously operated tumor were included. Patient cohorts receiving combined treatment Two case series reported the outcome data after FSRT treat- (i.e., surgery + SRS/FSRT) for novel tumors were excluded. ment and 17 after SRS treatment. The average loss of tumor Patient cohorts including patients with neurofibromatosis control leading to a new VS-targeted intervention was 4.8% type 2 (NF2) were excluded unless the NF2 patients could be for FSRT and 5.0% for SRS within the follow-up period specified and excluded from the study cohort and result data (Table 1). The tumor volumes/sizes were equal for the SRS or the ratio of NF2 patients in the cohort was so small that any and FSRT studies. All SRS studies had a median marginal influence on the overall outcome data of the cohort was con- dose of 12–13 Gy, and both FSRT studies had a median total sidered marginal. dose of 50 Gy in fractions of 1.8–2Gy(Supplementary When more than one publication was found reporting data Table S2). There was no apparent trend for loss of tumor from the same or partly overlapping patient cohorts, we re- control in relation to median follow-up times (Fig. 2). Since served the right to choose the largest, most recent or the most these were all uncontrolled cohort reports (i.e., S3 studies), no suitable publication for the purpose of this review for inclu- statistical meta-analysis was attempted. Potential reporting bi- sion. Other papers reporting data from the same patient cohort as was assessed using a funnel plot for the SRS case series were excluded. (Supplementary Fig. S1) and revealed approximately equal distribution of treatment failure leading to a new intervention, independent of study size. Primary end point Loss of tumor control as defined by author (i.e., radiolog- ical progression) showed similar results such as loss of control Primary end point was loss of tumor control defined as fre- leading to a new intervention (Supplementary Table S3). Only quency of patients requiring a new VS-targeted intervention one study reported any mortality due to tumor progression (i.e., re-treatment with SRS, FSRT or surgery). [17], in 4 of 440 patients. 1016 Acta Neurochir (2017) 159:1013–1021 Table 1 Loss of tumor control ratios for the respective studies defined Records idenfied in databases as need for a new targeted treatment against the vestibular schwannoma Embase n = 245 PubMed n = 663 Author (year) Treatment failure (leading to a new Web of Science n = 185 intervention) Cochrane n = 1 SRS FSRT Records rejected aer Unger et al. [52]3/60 screening of tles/abstract Iwai et al. [22]3/52 n = 997 Myrseth et al. [36]5/102 Hempel et al. [19]4/123 Full-text arcles assessed for Liu et al. [29]2/74 eligibility Chopra et al. [10]3/216 n = 97 Fukuoka et al. [15]12/157 Pollock et al. [44]13/293 Full-text arcles Nagano et al. [39]1/87 excluded, with reasons Roos et al. [48]2/84 short follow-up AND/OR Sun et al. [50]14/190 small cohort n = 39 duplicate cohort n = 23 Yomo et al. [56]8/154 other n = 17 Hasegawa et al. [16, 17]36/440 Kim et al. [24]0/60 Boari et al. [6] 11/379 Addional arcles idenfied through Mindermann et al. [33]17/235 reference crosscheck Wangerid et al. [53]9/128 n = 1 Aoyama et al. [2]13/201 Litre et al. [28]4/155 Studies included in qualitave Total 143/2834 (5.0%) 17/356 (4.8%) evaluaon n = 19 studies (12 SRS, 2 FSRT) reported quantitative data for cranial Fig. 1 Schematic overview of the number of identified records for the systematic steps of the review process. In total 19 papers fulfilled the nerve deterioration. The facial nerve deterioration was 3.6% for inclusion criteria with regard to definition of the primary end point, SRS and 11.2% for FSRT (Table 3), and the trigeminal nerve follow-up and size of the patient cohort deterioration was 6.0% for SRS and 8.4% for FSRT (Table 4). Hearing deterioration Post hoc subanalysis of case-control (S2) studies not fulfilling inclusion criteria Hearing deterioration after treatment was defined as deterio- ration from serviceable hearing (Gardner-Robertson I or II) to A number of non-randomized quantitative comparative studies non-serviceable hearing (Gardner-Robertson III-V) on the (S2) were identified in the literature search. Although none of treated side. Quantitative hearing data were available for 13 these fulfilled all inclusion criteria with regard to follow-up of the included studies (11 SRS, 2 FSRT). In total 52% of the time and definition of the primary end point to be included in SRS patients had serviceable hearing before treatment vs. the primary analysis, five of these still reported quantitative data 59% of the FSRT patients. The average deterioration ratio on loss of tumor control (as defined by the author). Since these for patients with serviceable hearing before treatment was reports contain comparative data for SRS and FSRT from sin- 49% for SRS and 45% for FSRT (Table 2). No apparent trend gle centers, a separate post-hoc subanalysis of these studies was for increasing hearing deterioration was discernable in relation still undertaken. None of these studies showed any significant to median follow-up times (Fig. 3). difference in tumor control between SRS and FSRT (Fig. 4). Facial and trigeminal nerve deterioration Facial and trigeminal nerve deterioration was defined as any Discussion new onset or worsening of previous facial paralysis, facial spasm, facial tingling or loss of sensation on the treated In the present systematic review, we aimed to investigate the side—either transient or permanent. Fourteen of the included current scientific support for the long-term effectiveness and Acta Neurochir (2017) 159:1013–1021 1017 10 10% % Fig. 2 Loss of tumor control Loss of tumor control (leading to new intervention) distributed according to median follow-up time for the included studies. No apparent trend for in- creasing failure was noted with 8% 8% longer follow-up times after 5years 6% 6% SRS SRS FSRT FSRT 4% 4% 2% 0% 50 60 70 80 90 100 110 120 130 Follow-up time (months) safety of SRS compared to FSRT for the treatment of unilat- We found no randomized controlled studies comparing eral VS. Nineteen case series met the inclusion criteria (17 SRS and FSRT for vestibular schwannomas. One study ini- STS and 2 FSRT) and were enrolled in the systematic review. tially attempted a randomized design [1], which had to be The primary end point was loss of tumor control necessitating abandoned because of patient expectations or physician’sbias. a new VS-targeted intervention and showed comparable re- Another study had a degree of Bpseudo-randomization^ based sults for SRS (mean 5.0%) and FSRT (mean 4.8%) in the on the dentate status, where patients were assigned to the included case series. Similar results were found when analyz- different treatment arms based on whether they could be reli- ing tumor control ratios as defined by the different authors ably and reproducibly fixated for FSRT or not [32]. However, regardless of the need for a new intervention. Thus, the current both of these studies were excluded from the main analysis data provide no indication of one treatment technique being because of the too short follow-up time. Also no other case- superior to the other with regard to tumor control. A caveat control studies comparing SRS and FSRT were found to be when analyzing these results is that only two FSRT studies eligible according to the inclusion criteria in the present sys- (reporting on a total of 356 patients) met the inclusion criteria tematic review. These studies were all either too small (<50 and also that these studies had a shorter follow-up time com- patients), reported too short follow-up times (<5 years) or did pared to several of the SRS studies (reporting on a total of not report on the primary end point (risk for a new interven- 2834 patients). This substantial gap in reported follow-up time tion) in a quantifiable manner. Some studies also allocated between centers using SRS or FSRT could merely represent patients differently to SRS or FSRT treatment based on tumor different follow-up traditions, but certainly indicates a risk of size and pretreatment hearing function, creating unbalanced detection bias in the FSRT group. One additional study [51] groups with respect to selection bias [11–13]. However, since was identified in the initial literature search reporting on these are likely the most Bcomparable^ groups available in the hypofractionated radiotherapy (HfRT) for VS using the literature, a separate post hoc analysis of comparative studies CyberKnife (18 Gy in 3 fractions). However, since HfRT from where quantitative data could be extracted was undertaken a radiobiologic point of view is likely to be mechanistically (Fig. 4), but showed no differences between SRS and FSRT more similar to SRS than to conventional FSRT, this study with regard to tumor control. These results are also in line with was not included in the FSRT group. This study showed a a recent large German multicenter report on long-term (medi- favorable outcome with no need for reintervention in any of an 67 months) follow-up after radiation therapy of VS [14], the 117 treated patients within the 61-month median follow- which showed equal tumor control ratios for SRS and FSRT up. Although promising, these results from a single study (this paper could not be included in the statistical analysis because of lack of quantifiable outcome data). would need to be additionally confirmed. 1018 Acta Neurochir (2017) 159:1013–1021 Table 2 Hearing deterioration Author (year) Gardner Robertson Ratio Gardner Robertson Ratio deteriorated for the 14 included studies with I+II deteriorated SRS I+II FSRT quantitative hearing data, defined as deterioration from serviceable Before After Before After (Gardner-Robertson I and II) to SRS SRS FSRT FSRT non-serviceable (Gardner- Robertson III–V) hearing Unger et al. [52] 29/29 16/29 13/29 Iwai et al. [22] 18/47 10/47 8/18 Myrseth et al. [36] 31/60 10/60 21/31 Chopra et al. [10] 106/162 61/162 45/106 Fukuoka et al. 59/152 42/152 17/59 [15] Roos et al. [48] 50/91 19/91 31/50 Sun et al. [50] 22/190 18/190 4/22 Yomo et al. [56] 110/154 64/154 46/110 Hasegawa et al. 135/345 46/345 46/135 [16, 17] Kim et al. [24] 60/60 34/60 26/60 Boari et al. [6] 96/96 47/96 47/96 Aoyama et al. [2] 77/77 43/77 34/77 Litre et al. [28] 61/158 33/158 28/61 Total 349/716 (49%) 62/138 (45%) As for all systematic reviews, the quality of the included radiation toxicity and hearing deterioration, usually emerge studies is the limiting factor. When analyzing results of treat- within the first years after treatment, and these safety end points ment efficacy for benign tumors, long-term follow-up is of are therefore less sensitive to short follow-up times. essential importance. In the case of vestibular schwannomas, To be certain of a robust primary end point that was indepen- tumor control on the order of up to 70% after 1–3years canalso dent of subjective evaluation and did not differ substantially be- be expected with conservative management [49]. Remarkably tween centers, we used the need for a new intervention instead of many reports had to be excluded from this review because of radiological loss of tumor control. Progression necessitating a the short follow-up time. Complications, such as cranial nerve new intervention is also the most clinically relevant end point, 80% 80% Hearing deterioration Fig. 3 Hearing deterioration ratios distributed according to median follow-up time for the in- 70% 70% cluded studies. No apparent trend for increasing deterioration ratios was noted with longer follow-up 60% 60% times after 5 years 50% 50% SRS SRS FSRT FSRT 40% 40% 30% 30% 20% 10% 0% 50 60 70 80 90 100 110 120 130 Follow-up time (months) Acta Neurochir (2017) 159:1013–1021 1019 Table 3 Facial nerve deterioration defined as any transient or permanent impairment of facial nerve function, either new or worsening of preexisting symptoms Author (year) Facial nerve deterioration SRS FSRT Unger et al. [52]5/60 Iwai et al. [22]3/52 Hempel et al. [19]0/123 Liu et al. [29]3/63 Fig. 4 Odds ratios with 95% CI for five single-center comparative stud- Chopra et al. [10]0/216 ies comparing loss of tumor control after SRS compared to FSRT Fukuoka et al. [15]2/157 Roos et al. [48]9/102 measure, such as the need for a new intervention, also need to Sun et al. [50]28/190 be powered enough to detect these rare events. For this reason, Yomo et al. [56]1/154 studies reporting fewer than 50 patients were excluded. Multiple Hasegawa et al. [16, 17]7/440 studies also had to be excluded because of reporting data from Boari et al. [6] 11/379 the same or partly overlapping patient cohorts. Redundant pub- Wangerid et al. [53]5/128 lishing of patient data constitutes a problematic issue in the con- Aoyama et al. [2]19/201 text of systematic reviews, since this is rarely cross-referenced in Litre et al. [28]21/155 the reports and thus increases the risk of duplicate publication Total 74/2064 (3.6%) 40/356 (11.2%) bias [20]. One of the major benefits of FSRT or SRS in comparison to MS for VS is the decreased risk of cranial nerve damage. There since an increase in tumor volume (pseudoprogression) after ra- was a small difference in patients with serviceable hearing before diation therapy is common and is seldom symptomatic [18]. treatment between groups (SRS 52% vs. FSRT 59%). This may However, several of the reviewed articles reported only on radio- reflect the tendency in some centers to refer patients with service- logical tumor progression, without any data on the need for new able hearing to FSRT [11–13]. The hearing deterioration showed treatments in these patients and were therefore excluded from this no substantial difference between the FSRT group (45%) com- review. Furthermore, studies using a dichotomous outcome pared to SRS (49%). Since these data are based on uncontrolled case series, no analysis of statistical significance was undertaken. Table 4 Trigeminal nerve deterioration defined as any transient or Contrary to what has previously been reported in some permanent impairment of trigeminal nerve function, either novel or single-center comparative studies [11, 26, 32], an increased worsening of preexisting symptoms risk of facial and trigeminal nerve deterioration was found in Author (year) Trigeminal nerve deterioration the included FRST studies compared to studies on SRS (Tables 3 and 4). For the purpose of this review, all reported SRS FSRT symptoms of nerve deterioration—mild and transient as well as permanent—were included in the analysis. Unger et al. [52]3/60 Iwai et al. [22]2/52 Hempel et al. [19]7/121 Liu et al. [29]5/74 Conclusion Chopra et al. [10]8/216 We identified several studies reporting the long-term tumor con- Fukuoka et al. [15]7/159 trol rate after SRS, while only two studies reported on long-term Roos et al. [48]15/102 tumor control after FSRT could be identified, engendering a more Sun et al. [50]44/190 robust support for favorable long-term tumor control with SRS. Yomo et al. [56]2/154 The risk for facial and trigeminal nerve deterioration was less for Hasegawa et al. [16, 17]3/440 patients treated in the SRS series compared to VS patients receiv- Boari et al. [6]26/379 ing FSRT, while the chance of preserved hearing showed no Wangerid et al. [53]3/128 difference between the two treatment groups. To establish guide- Aoyama et al. [2] 23/201 lines for radiotherapeutic treatment in vestibular schwannomas, a Litre et al. [28]7/155 RCT or a prospective controlled study comparing SRS and FSRT Total 125/2075 (6.0%) 30/356 (8.4%) would be needed. While awaiting results from such a study, this 1020 Acta Neurochir (2017) 159:1013–1021 series of unilateral vestibular nerve schwannoma surgical patients review reveals a need for FSRTcase series with larger cohorts and (acoustic neuroma). Surg Neurol 39:485–493 longer follow-up tim to obtain more solid data on long-term tumor 9. Chan AW, Black P, Ojemann RG, Barker FG 2nd, Kooy HM, Lopes control for this treatment modality. VV, McKenna MJ, Shrieve DC, Martuza RL, Loeffler JS (2005) Stereotactic radiotherapy for vestibular schwannomas: favorable out- come with minimal toxicity. Neurosurgery 57:60–70 discussion 60-70 Acknowledgements We express our gratitude to Eva Fjällgren at the Karolinska University Hospital library for extensive help with the sys- 10. Chopra R, Kondziolka D, Niranjan A, Lunsford LD, Flickinger JC tematic literature search. (2007) Long-term follow-up of acoustic schwannoma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys 68:845–851 Compliance with ethical standards 11. Choy W, Spasic M, Pezeshkian P, Fong BM, Nagasawa DT, Trang A, Mathur I, De Salles A, Gorgulho A, Selch M, Gopen QS, Yang I Funding No funding was received for this research. (2013) Outcomes of stereotactic radiosurgery and stereotactic radio- therapy for the treatment of vestibular schwannoma. Neurosurgery Conflict of interest None. 60:120–125 12. Chung HT, Ma R, Toyota B, Clark B, Robar J, McKenzie M (2004) Ethical approval All procedures performed in studies involving hu- Audiologic and treatment outcomes after linear accelerator-based man participants were in accordance with the ethical standards of the stereotactic irradiation for acoustic neuroma. Int J Radiat Oncol institutional and/or national research committee and with the 1964 Biol Phys 59:1116–1121 Helsinki Declaration and its later amendments or comparable ethical 13. Combs SE, Welzel T, Kessel K, Habermehl D, Rieken S, Schramm O, standards. For this type of study formal consent is not required. 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Lin D, Hegarty JL, Fischbein NJ, Jackler RK (2005) The preva- lence of Bincidental^ acoustic neuroma. Arch Otolaryngol Head Sitathanee C, Sawangsilpa T, Janwityanujit T, Yongvithisatid P, Neck Surg 131:241–244 (2014) Linac-based stereotactic radiosurgery and fractionated ste- 28. Litre F, Rousseaux P, Jovenin N, Bazin A, Peruzzi P, Wdowczyk D, reotactic radiotherapy for vestibular schwannomas: comparative Colin P (2013) Fractionated stereotactic radiotherapy for acoustic observations of 139 patients treated at a single institution. J neuromas: a prospective monocenter study of about 158 cases. Radiat Res 55:351-358 Radiother Oncol J Eur Soc Ther Radiol Oncol 106:169–174 46. Regis J, Pellet W, Delsanti C, Dufour H, Roche PH, Thomassin JM, Zanaret M, Peragut JC (2002) Functional outcome after Gamma 29. Liu D, Xu D, Zhang Z, Zhang Y, Zheng L (2006) Long-term out- comes after Gamma Knife surgery for vestibular schwannomas: a 10- Knife surgery or microsurgery for vestibular schwannomas. J year experience. J Neurosurg 105(Suppl):149–153 Neurosurg 97:1091–1100 47. Regis J, Tamura M, Delsanti C, Roche PH, Pellet W, Thomassin JM 30. Lobato-Polo J, Kondziolka D, Zorro O, Kano H, Flickinger JC, Lunsford LD (2009) Gamma Knife radiosurgery in younger pa- (2008) Hearing preservation in patients with unilateral vestibular schwannoma after Gamma Knife surgery. Prog Neurol Surg 21: tients with vestibular schwannomas. Neurosurgery 65:294–300 dis- cussion 300-291 142–151 48. Roos DE, Potter AE, Zacest AC (2011) Hearing preservation after 31. Massick DD, Welling DB, Dodson EE, Scholfield M, Nagaraja HN, Schmalbrock P, Chakeres DW (2000) Tumor growth and audiomet- low dose LINAC radiosurgery for acoustic neuroma depends on ric change in vestibular schwannomas managed conservatively. initial hearing and time. Radiother Oncol J Eur Soc Ther Radiol Laryngoscope 110:1843–1849 Oncol 101:420–424 32. Meijer OWM, Vandertop WP, Baayen JC, Slotman BJ (2003) 49. Stangerup SE, Caye-Thomasen P (2012) Epidemiology and natural history of vestibular schwannomas. Otolaryngol Clin N Am 45: Single-fraction vs. fractionated LINAC-based stereotactic radiosur- gery for vestibular schwannoma: a single-institution study. Int J 257–268 vii Radiat Oncol Biol Phys 56:1390–1396 50. Sun S, Liu A (2012) Long-term follow-up studies of Gamma Knife surgery with a low margin dose for vestibular schwannoma. J 33. Mindermann T, Schlegel I (2014) How to distinguish tumor growth from transient expansion of vestibular schwannomas following Neurosurg 117(Suppl):57–62 Gamma Knife radiosurgery. Acta Neurochir 156:1121–1123 51. Tsai JT, Lin JW, Lin CM, Chen YH, Ma HI, Jen YM, Chen YH, Ju 34. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred DT (2013) Clinical evaluation of CyberKnife in the treatment of vestibular schwannomas. Biomed Res Int 2013:297093 reporting items for systematic reviews and meta-analyses: the 52. Unger F, Walch C, Papaefthymiou G, Eustacchio S, Feichtinger K, PRISMA statement. BMJ (Clin Res Ed) 339:b2535 Quehenberger F, Pendl G (2002) Long term results of radiosurgery 35. Muzevic D, Legcevic J, Splavski B, Caye-Thomasen P (2014) for vestibular schwannomas. Zentralbl Neurochir 63:52–58 Stereotactic radiotherapy for vestibular schwannoma. Cochrane Database Syst Rev. doi:10.1002/14651858.CD009897.pub2 53. Wangerid T, Bartek J Jr, Svensson M, Forander P (2014) Long-term quality of life and tumour control following Gamma Knife radiosur- 36. Myrseth E, Moller P, Pedersen PH, Vassbotn FS, Wentzel-Larsen T, Lund-Johansen M (2005) Vestibular schwannomas: clinical results gery for vestibular schwannoma. Acta Neurochir 156:389–396 54. Wangerid T, Benmakhlouf H, Grane P, Bartek J Jr, Svensson M, and quality of life after microsurgery or Gamma Knife radiosurgery. Forander P (2015) Implication of using MRI co-registered with CT Neurosurgery 56:927–935 discussion 927-935 in Leksell Gamma Knife® dose planning for patients with vestibu- 37. Myrseth E, Pedersen PH, Moller P, Lund-Johansen M (2007) lar schwannoma. Clin Neurol Neurosurg 138:10–15 Treatment of vestibular schwannomas. Why, when and how? Acta Neurochir 149:647–660 discussion 660 55. Wolbers JG, Dallenga AH, Mendez Romero A, van Linge A (2013) What intervention is best practice for vestibular schwannomas? A 38. Myrseth E, Moller P, Pedersen PH, Lund-Johansen M (2009) systematic review of controlled studies. BMJ Open 3:e001345 Vestibular schwannoma: surgery or Gamma Knife radiosurgery? 56. Yomo S, Carron R, Thomassin JM, Roche PH, Regis J (2012) A prospective, nonrandomized study. Neurosurgery 64:654–661 Longitudinal analysis of hearing before and after radiosurgery for discussion 661-653 vestibular schwannoma. J Neurosurg 117:877–885 39. Nagano O, Serizawa T, Higuchi Y, Matsuda S, Sato M, Yamakami I, Okiyama K, Ono J, Saeki N (2010) Tumor shrinkage of vestibular schwannomas after Gamma Knife surgery: results after more than 5 years of follow-up. J Neurosurg 113(Suppl):122–127 Comments 40. Nakazawa H, Mori Y, Komori M, Shibamoto Y, Tsugawa T, The best management for vestibular schwannoma remains a never- Kobayashi T, Hashizume C (2014) Validation of accuracy in image ending controversy. Our decisions must rely on scientific evidence, but it co-registration with computed tomography and magnetic resonance may be difficult because management is often based on local practice. imaging in Gamma Knife radiosurgery. J Radiat Res 55:924–933 Nearly all reports are Bsingle treatment, single center,^ and very few high- 41. Pawlik TM, Keyomarsi K (2004) Role of cell cycle in mediating quality comparative studies exist. It is a difficult challenge for the neuro- sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 59:928–942 surgical community to conduct multicenter comparative studies on VS. 42. Pollock BE, Lunsford LD, Kondziolka D, Flickinger JC, Bissonette Still, we owe this to our patients to provide them with the best treatment. DJ, Kelsey SF, Jannetta PJ (1995) Outcome analysis of acoustic Morten Lund-Johansen neuroma management: a comparison of microsurgery and stereo- tactic radiosurgery. Neurosurgery 36:215–224 discussion 224-219 Bergen, Norway. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Neurochirurgica Pubmed Central

Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients: a systematic review

Acta Neurochirurgica , Volume 159 (6) – Apr 13, 2017

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© The Author(s) 2017
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0001-6268
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10.1007/s00701-017-3164-6
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Abstract

Acta Neurochir (2017) 159:1013–1021 DOI 10.1007/s00701-017-3164-6 REVIEW ARTICLE - BRAIN TUMORS Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients: a systematic review 1 1,2,3 4 2,5 Oscar Persson & Jiri Bartek Jr. & Netanel Ben Shalom & Theresa Wangerid & 6,7,8 1,2 Asgeir Store Jakola & Petter Förander Received: 20 November 2016 /Accepted: 27 March 2017 /Published online: 13 April 2017 The Author(s) 2017. This article is an open access publication Abstract Publications from 1995 through 2014 with a minimum of 50 Objective Repeated controlled studies have revealed that ste- adult (>18 years) patients with unilateral VS, followed for a reotactic radiosurgery is better than microsurgery for patients median of >5 years, were eligible for inclusion. After screen- with vestibular schwannoma (VS) <3 cm in need of interven- ing titles and abstracts of the 1094 identified articles and sys- tion. In this systematic review we aimed to compare results tematically reviewing 98 of these articles, 19 were included. from single-fraction stereotactic radiosurgery (SRS) to fraction- Intervention Patients with unilateral VS treated with radiosur- ated stereotactic radiotherapy (FSRT) for patients with VS. gery were compared to patients treated with fractionated ste- Data sources and eligibility criteria We systematically reotactic radiotherapy. searched MEDLINE, Web of Science, Embase and Results No randomized controlled trial (RCT) was identified. Cochrane and screened relevant articles for references. None of the identified controlled studies comparing SRS with FSRT were eligible according to the inclusion criteria. Nineteen case series on SRS (n = 17) and FSRT (n =2)were included in the systematic review. Loss of tumor control ne- Electronic supplementary material The online version of this article cessitating a new VS-targeted intervention was found in an (doi:10.1007/s00701-017-3164-6) contains supplementary material, average of 5.0% of the patients treated with SRS and in which is available to authorized users. 4.8% treated with FSRT. Mean deterioration ratio for patients * Oscar Persson with serviceable hearing before treatment was 49% for SRS oscar.persson@sll.se and 45% for FSRT, respectively. The risk for facial nerve deterioration was 3.6% for SRS and 11.2% for FSRT and for 1 trigeminal nerve deterioration 6.0% for SRS and 8.4% for Department of Neurosurgery R03:02, Karolinska University FSRT. Since these results were obtained from case series, a Hospital, 171 76 Stockholm, Sweden 2 regular meta-analysis was not attempted. Department of Clinical Neuroscience, Karolinska Institutet, Conclusion SRS and FSRT are both noninvasive treatment Stockholm, Sweden 3 alternatives for patients with VS with low rates of treatment Department of Neurosurgery, Copenhagen University Hospital failure in need of rescue therapy. In this selection of patients, Rigshospitalet, Copenhagen, Denmark 4 the progression-free survival rates were on the order of 92– Department of Neurosurgery, Rabin Medical Center, Petah 100% for both treatment options. There is a lack of high- Tikva, Israel quality studies comparing radiation therapy alternatives for pa- Department of Neurology, St; Göran Hospital, Stockholm, Sweden tients with VS. Finally, 19 articles reported long-term tumor Department of Neurosurgery, St. Olavs Hospital, control after SRS, while only 2 articles reported long-term 7006 Trondheim, Norway FSRT results, making effect estimates more uncertain for FSRT. Department of Neurosurgery, Sahlgrenska University Hospital, Blå Stråket 5, vån 3, 41345 Göteborg, Sweden 8 Keywords Vestibular schwannoma Stereotactic Department of Clinical Neuroscience, Institute of Neuroscience and . . radiosurgery Fractionated stereotactic radiotherapy Gamma Physiology, Sahlgrenska Academy, Box 430, 40530 Göteborg, Sweden Knife LINAC 1014 Acta Neurochir (2017) 159:1013–1021 Introduction of the cell cycle [41]. On the contrary, SRS relies on a single high radiation dose, potentially affecting tumor cells also in Vestibular schwannomas (VSs) are benign intracranial tumors the non-dividing phase. Physical properties of Gamma Knife arising from the Schwann cells of the eight cranial nerve. The SRS allow a steep radiation gradient on the tumor margin, incidence has been reported to be approximately 2 in 100,000 which is important for keeping the dose to adjacent structures [21, 27, 31, 49]. Although benign, these tumors have the abil- low. While it is known that some tumors resistant to fraction- ity to grow and can cause significant symptoms due to com- ated radiotherapy may responds to radiosurgery, the precise pression of the cerebellum or brain stem or impairment of the differences of the radiobiological properties of the two modal- vestibulocochlear nerve function. Once the VS is discovered, ities are to some extent still an issue of discussion [25]. With symptoms like unilateral sensorineural hearing loss, vertigo the evolution of hypfractionated regimes a continuum has also and tinnitus can usually be traced back several years [37]. emerged between radiotherapy and radiosurgery, and some- Three different management strategies are commonly ap- times the distinction might be unclear. The most widely ac- plied after a diagnosis of VS. Conservative management in- cepted definition of what constitutes radiosurgery seems to be cluding regular scheduled magnetic resonance imaging (MRI) that of the AANS/CNS, defining radiosurgery as a maximum and audiometry is frequently used for small asymptomatic of five treatment sessions (however typically performed in a tumors. If the VS show signs of growth, or in case of neuro- single session) [4]. logical deterioration, treatment with microsurgery (MS) or A stereotactic frame is always used for Gamma Knife SRS, radiosurgery is considered. MS is the method of choice for which further enhances the precision of the delivered radia- large tumors with radiological or neurological signs of tion, and no margin is needed to compensate for movement of brainstem compression. Nowadays, MS can be performed the head [54]. However, this set-up may be perceived as more with low mortality, but it is still associated with a significant cumbersome and invasive. There is no consensus in the liter- risk of neurological sequelae such as hearing loss and facial ature on the definition of Bstereotactic^ fractionated radiother- nerve palsy [3, 5, 7, 8]. Single-dose stereotactic radiosurgery apy. However, all reports concerning FSRT subsequently in- (SRS) and fractionated stereotactic radiotherapy (FSRT) cluded in this review utilized LINAC-based systems using aiming to arrest tumor growth are the most commonly used either face masks or relocatable frames for fixation, and all noninvasive alternatives. In case series of patients suitable for used this terminology, which is why this has also been adopted radiosurgery/radiotherapy, the progression-free survival rates for this review. are comparable to those of case series of microsurgical resec- Since there is a lack of high evidence studies comparing the tion of VS [14, 16, 30, 53]. Further, controlled studies and different radiation modalities, local treatment policies and subsequent systematic reviews support the use of radiosurgery availability have determined the choice of irradiation modali- ty. In the present systematic review, we aim to study the ef- in VS patients eligible for both surgery and radiosurgery [23, 36, 38, 42, 43, 46]. Additionally, SRS and FSRTentail a lower fectiveness and safety of SRS compared to FSRT for the treat- incidence of side effects such as facial nerve palsy and hearing ment of unilateral VS. deterioration [9, 47]. In a recent Cochrane review [35]of controlled randomized trials, the authors concluded that there was insufficient evidence to recommend either surgical or radiation therapy in the treatment of VS. However, six pro- Methods spective intervention studies comparing MS to SRS all con- cluded that SRS demonstrates similar effectiveness in terms of The study was carried out based on the recommendations progression-free survival and that SRS demonstrates a signif- outlined in the Cochrane Handbook for Systematic Reviews icantly lower risk of neurological deteriorations such as facial of Interventions [20]. The review protocol was conducted ac- nerve palsies [23, 36, 38, 42, 43, 46]. Results of these studies cording to the PRISMA statement [34] and registered in were analyzed in a systematic review comparing Gamma PROSPERO International Prospective Register of Knife radiosurgery with microsurgical resection in VS eligible Systematic Reviews (registration no. CRD 42015029505). for both treatments and demonstrated better outcome after Five databases—EMBASE, MEDLINE, Web of Science, Gamma Knife radiosurgery [40, 55]. clinicaltrials.gov and the Cochrane library—were There are some different advantages/disadvantages related systematically searched for records concerning SRS and/or to the radiation techniques in SRS and FSRT. Linear acceler- FSRT for the treatment of VS published between January ator (LINAC)-based systems for FSRTare more available, and 1995 and December 2014. The systematic search was execut- due to the low fractionation dose, larger tumors can be treated. ed with Medical Subject Headings (MeSH) terms if available The theoretical rationale for dividing the prescribed total dose or as free text. The searches were performed from January 28– into 25–30 fractions is mainly to increase the chance of February 2 2015. The specific search criteria are available in targeting the tumor cells in the most radiation-sensitive phase Supplementary Table S1. Acta Neurochir (2017) 159:1013–1021 1015 An initial review of eligibility and relevance was per- Secondary end points formed based on abstracts for all records by the senior author (PF). In the second round all remaining records were review Secondary end points were: frequency of death due to tumor according to a Systematic Review Form (SRF) by two authors progression; frequency of VS patients with functional hearing independently (PF and OP, or JB and NBS). Reference lists of [Gardner Roberson (GR) class 1 and 2] deteriorating to non- the reviewed papers were crosschecked for further publica- serviceable hearing (GR class 3–5); frequency of loss of tumor tions of relevance. Statistical calculations were performed control as defined by the authors; frequency of patients with using the MedCalc tool (www.medcalc.org/calc). deterioration of facial nerve function after treatment; frequen- End points were dichotomous and are presented as frequen- cy of patients with deterioration of trigeminal nerve function cies and odds ratios (OR) with 95% confidence intervals (CI). after treatment. Regular meta-analyses were not attempted for uncontrolled case series. Results were instead reported as summarized fre- quencies for the individual end points without considering Results heterogeneity between studies. Literature search Inclusion and exclusion criteria The initial literature search yielded 1094 records after dupli- cate results had been eliminated (Fig. 1 and Supplementary Studies on adults (≥18 years) including patients with a minimal Table S1). The initial review could discard 997 records as not median (if the median was not reported, mean was used) relevant to the topic or as inadequate regarding cohort size or follow-up of 5 years, with unilateral VS (diagnosed with histo- follow-up time, and after reference cross-check 98 records pathology or typical MR appearance) published in the period were reviewed according to a systematic review protocol. 1995–2014 and treated with either SRS or FSRTwere included. After the second review round a final 19 records were found Included studies were categorized according to the follow- to fulfill all inclusion criteria [2, 6, 10, 15, 17, 19, 22, 24, 28, ing: S1, randomized controlled trials (RCTs), quasi-RCTs of 29, 33, 36, 39, 44, 48, 50, 52, 53, 56]. No randomized studies any sample size; S2, quantitative comparative study designs (S1) were identified on the subject. A number of non- not being prospective randomized studies, but including co- randomized quantitative comparative studies (S2) were found; hort studies and case control studies with ≥50 patients in total however, none of them fulfilled all criteria regarding follow- with a median follow-up time of >5 years; S3, case series with up time and/or defining the primary outcome parameter. ≥50 patients and a median follow-up time of >5 years. Papers concerning patient cohorts treated with SRS or FSRT Tumor control for novel tumors or regrowth of a previously operated tumor were included. Patient cohorts receiving combined treatment Two case series reported the outcome data after FSRT treat- (i.e., surgery + SRS/FSRT) for novel tumors were excluded. ment and 17 after SRS treatment. The average loss of tumor Patient cohorts including patients with neurofibromatosis control leading to a new VS-targeted intervention was 4.8% type 2 (NF2) were excluded unless the NF2 patients could be for FSRT and 5.0% for SRS within the follow-up period specified and excluded from the study cohort and result data (Table 1). The tumor volumes/sizes were equal for the SRS or the ratio of NF2 patients in the cohort was so small that any and FSRT studies. All SRS studies had a median marginal influence on the overall outcome data of the cohort was con- dose of 12–13 Gy, and both FSRT studies had a median total sidered marginal. dose of 50 Gy in fractions of 1.8–2Gy(Supplementary When more than one publication was found reporting data Table S2). There was no apparent trend for loss of tumor from the same or partly overlapping patient cohorts, we re- control in relation to median follow-up times (Fig. 2). Since served the right to choose the largest, most recent or the most these were all uncontrolled cohort reports (i.e., S3 studies), no suitable publication for the purpose of this review for inclu- statistical meta-analysis was attempted. Potential reporting bi- sion. Other papers reporting data from the same patient cohort as was assessed using a funnel plot for the SRS case series were excluded. (Supplementary Fig. S1) and revealed approximately equal distribution of treatment failure leading to a new intervention, independent of study size. Primary end point Loss of tumor control as defined by author (i.e., radiolog- ical progression) showed similar results such as loss of control Primary end point was loss of tumor control defined as fre- leading to a new intervention (Supplementary Table S3). Only quency of patients requiring a new VS-targeted intervention one study reported any mortality due to tumor progression (i.e., re-treatment with SRS, FSRT or surgery). [17], in 4 of 440 patients. 1016 Acta Neurochir (2017) 159:1013–1021 Table 1 Loss of tumor control ratios for the respective studies defined Records idenfied in databases as need for a new targeted treatment against the vestibular schwannoma Embase n = 245 PubMed n = 663 Author (year) Treatment failure (leading to a new Web of Science n = 185 intervention) Cochrane n = 1 SRS FSRT Records rejected aer Unger et al. [52]3/60 screening of tles/abstract Iwai et al. [22]3/52 n = 997 Myrseth et al. [36]5/102 Hempel et al. [19]4/123 Full-text arcles assessed for Liu et al. [29]2/74 eligibility Chopra et al. [10]3/216 n = 97 Fukuoka et al. [15]12/157 Pollock et al. [44]13/293 Full-text arcles Nagano et al. [39]1/87 excluded, with reasons Roos et al. [48]2/84 short follow-up AND/OR Sun et al. [50]14/190 small cohort n = 39 duplicate cohort n = 23 Yomo et al. [56]8/154 other n = 17 Hasegawa et al. [16, 17]36/440 Kim et al. [24]0/60 Boari et al. [6] 11/379 Addional arcles idenfied through Mindermann et al. [33]17/235 reference crosscheck Wangerid et al. [53]9/128 n = 1 Aoyama et al. [2]13/201 Litre et al. [28]4/155 Studies included in qualitave Total 143/2834 (5.0%) 17/356 (4.8%) evaluaon n = 19 studies (12 SRS, 2 FSRT) reported quantitative data for cranial Fig. 1 Schematic overview of the number of identified records for the systematic steps of the review process. In total 19 papers fulfilled the nerve deterioration. The facial nerve deterioration was 3.6% for inclusion criteria with regard to definition of the primary end point, SRS and 11.2% for FSRT (Table 3), and the trigeminal nerve follow-up and size of the patient cohort deterioration was 6.0% for SRS and 8.4% for FSRT (Table 4). Hearing deterioration Post hoc subanalysis of case-control (S2) studies not fulfilling inclusion criteria Hearing deterioration after treatment was defined as deterio- ration from serviceable hearing (Gardner-Robertson I or II) to A number of non-randomized quantitative comparative studies non-serviceable hearing (Gardner-Robertson III-V) on the (S2) were identified in the literature search. Although none of treated side. Quantitative hearing data were available for 13 these fulfilled all inclusion criteria with regard to follow-up of the included studies (11 SRS, 2 FSRT). In total 52% of the time and definition of the primary end point to be included in SRS patients had serviceable hearing before treatment vs. the primary analysis, five of these still reported quantitative data 59% of the FSRT patients. The average deterioration ratio on loss of tumor control (as defined by the author). Since these for patients with serviceable hearing before treatment was reports contain comparative data for SRS and FSRT from sin- 49% for SRS and 45% for FSRT (Table 2). No apparent trend gle centers, a separate post-hoc subanalysis of these studies was for increasing hearing deterioration was discernable in relation still undertaken. None of these studies showed any significant to median follow-up times (Fig. 3). difference in tumor control between SRS and FSRT (Fig. 4). Facial and trigeminal nerve deterioration Facial and trigeminal nerve deterioration was defined as any Discussion new onset or worsening of previous facial paralysis, facial spasm, facial tingling or loss of sensation on the treated In the present systematic review, we aimed to investigate the side—either transient or permanent. Fourteen of the included current scientific support for the long-term effectiveness and Acta Neurochir (2017) 159:1013–1021 1017 10 10% % Fig. 2 Loss of tumor control Loss of tumor control (leading to new intervention) distributed according to median follow-up time for the included studies. No apparent trend for in- creasing failure was noted with 8% 8% longer follow-up times after 5years 6% 6% SRS SRS FSRT FSRT 4% 4% 2% 0% 50 60 70 80 90 100 110 120 130 Follow-up time (months) safety of SRS compared to FSRT for the treatment of unilat- We found no randomized controlled studies comparing eral VS. Nineteen case series met the inclusion criteria (17 SRS and FSRT for vestibular schwannomas. One study ini- STS and 2 FSRT) and were enrolled in the systematic review. tially attempted a randomized design [1], which had to be The primary end point was loss of tumor control necessitating abandoned because of patient expectations or physician’sbias. a new VS-targeted intervention and showed comparable re- Another study had a degree of Bpseudo-randomization^ based sults for SRS (mean 5.0%) and FSRT (mean 4.8%) in the on the dentate status, where patients were assigned to the included case series. Similar results were found when analyz- different treatment arms based on whether they could be reli- ing tumor control ratios as defined by the different authors ably and reproducibly fixated for FSRT or not [32]. However, regardless of the need for a new intervention. Thus, the current both of these studies were excluded from the main analysis data provide no indication of one treatment technique being because of the too short follow-up time. Also no other case- superior to the other with regard to tumor control. A caveat control studies comparing SRS and FSRT were found to be when analyzing these results is that only two FSRT studies eligible according to the inclusion criteria in the present sys- (reporting on a total of 356 patients) met the inclusion criteria tematic review. These studies were all either too small (<50 and also that these studies had a shorter follow-up time com- patients), reported too short follow-up times (<5 years) or did pared to several of the SRS studies (reporting on a total of not report on the primary end point (risk for a new interven- 2834 patients). This substantial gap in reported follow-up time tion) in a quantifiable manner. Some studies also allocated between centers using SRS or FSRT could merely represent patients differently to SRS or FSRT treatment based on tumor different follow-up traditions, but certainly indicates a risk of size and pretreatment hearing function, creating unbalanced detection bias in the FSRT group. One additional study [51] groups with respect to selection bias [11–13]. However, since was identified in the initial literature search reporting on these are likely the most Bcomparable^ groups available in the hypofractionated radiotherapy (HfRT) for VS using the literature, a separate post hoc analysis of comparative studies CyberKnife (18 Gy in 3 fractions). However, since HfRT from where quantitative data could be extracted was undertaken a radiobiologic point of view is likely to be mechanistically (Fig. 4), but showed no differences between SRS and FSRT more similar to SRS than to conventional FSRT, this study with regard to tumor control. These results are also in line with was not included in the FSRT group. This study showed a a recent large German multicenter report on long-term (medi- favorable outcome with no need for reintervention in any of an 67 months) follow-up after radiation therapy of VS [14], the 117 treated patients within the 61-month median follow- which showed equal tumor control ratios for SRS and FSRT up. Although promising, these results from a single study (this paper could not be included in the statistical analysis because of lack of quantifiable outcome data). would need to be additionally confirmed. 1018 Acta Neurochir (2017) 159:1013–1021 Table 2 Hearing deterioration Author (year) Gardner Robertson Ratio Gardner Robertson Ratio deteriorated for the 14 included studies with I+II deteriorated SRS I+II FSRT quantitative hearing data, defined as deterioration from serviceable Before After Before After (Gardner-Robertson I and II) to SRS SRS FSRT FSRT non-serviceable (Gardner- Robertson III–V) hearing Unger et al. [52] 29/29 16/29 13/29 Iwai et al. [22] 18/47 10/47 8/18 Myrseth et al. [36] 31/60 10/60 21/31 Chopra et al. [10] 106/162 61/162 45/106 Fukuoka et al. 59/152 42/152 17/59 [15] Roos et al. [48] 50/91 19/91 31/50 Sun et al. [50] 22/190 18/190 4/22 Yomo et al. [56] 110/154 64/154 46/110 Hasegawa et al. 135/345 46/345 46/135 [16, 17] Kim et al. [24] 60/60 34/60 26/60 Boari et al. [6] 96/96 47/96 47/96 Aoyama et al. [2] 77/77 43/77 34/77 Litre et al. [28] 61/158 33/158 28/61 Total 349/716 (49%) 62/138 (45%) As for all systematic reviews, the quality of the included radiation toxicity and hearing deterioration, usually emerge studies is the limiting factor. When analyzing results of treat- within the first years after treatment, and these safety end points ment efficacy for benign tumors, long-term follow-up is of are therefore less sensitive to short follow-up times. essential importance. In the case of vestibular schwannomas, To be certain of a robust primary end point that was indepen- tumor control on the order of up to 70% after 1–3years canalso dent of subjective evaluation and did not differ substantially be- be expected with conservative management [49]. Remarkably tween centers, we used the need for a new intervention instead of many reports had to be excluded from this review because of radiological loss of tumor control. Progression necessitating a the short follow-up time. Complications, such as cranial nerve new intervention is also the most clinically relevant end point, 80% 80% Hearing deterioration Fig. 3 Hearing deterioration ratios distributed according to median follow-up time for the in- 70% 70% cluded studies. No apparent trend for increasing deterioration ratios was noted with longer follow-up 60% 60% times after 5 years 50% 50% SRS SRS FSRT FSRT 40% 40% 30% 30% 20% 10% 0% 50 60 70 80 90 100 110 120 130 Follow-up time (months) Acta Neurochir (2017) 159:1013–1021 1019 Table 3 Facial nerve deterioration defined as any transient or permanent impairment of facial nerve function, either new or worsening of preexisting symptoms Author (year) Facial nerve deterioration SRS FSRT Unger et al. [52]5/60 Iwai et al. [22]3/52 Hempel et al. [19]0/123 Liu et al. [29]3/63 Fig. 4 Odds ratios with 95% CI for five single-center comparative stud- Chopra et al. [10]0/216 ies comparing loss of tumor control after SRS compared to FSRT Fukuoka et al. [15]2/157 Roos et al. [48]9/102 measure, such as the need for a new intervention, also need to Sun et al. [50]28/190 be powered enough to detect these rare events. For this reason, Yomo et al. [56]1/154 studies reporting fewer than 50 patients were excluded. Multiple Hasegawa et al. [16, 17]7/440 studies also had to be excluded because of reporting data from Boari et al. [6] 11/379 the same or partly overlapping patient cohorts. Redundant pub- Wangerid et al. [53]5/128 lishing of patient data constitutes a problematic issue in the con- Aoyama et al. [2]19/201 text of systematic reviews, since this is rarely cross-referenced in Litre et al. [28]21/155 the reports and thus increases the risk of duplicate publication Total 74/2064 (3.6%) 40/356 (11.2%) bias [20]. One of the major benefits of FSRT or SRS in comparison to MS for VS is the decreased risk of cranial nerve damage. There since an increase in tumor volume (pseudoprogression) after ra- was a small difference in patients with serviceable hearing before diation therapy is common and is seldom symptomatic [18]. treatment between groups (SRS 52% vs. FSRT 59%). This may However, several of the reviewed articles reported only on radio- reflect the tendency in some centers to refer patients with service- logical tumor progression, without any data on the need for new able hearing to FSRT [11–13]. The hearing deterioration showed treatments in these patients and were therefore excluded from this no substantial difference between the FSRT group (45%) com- review. Furthermore, studies using a dichotomous outcome pared to SRS (49%). Since these data are based on uncontrolled case series, no analysis of statistical significance was undertaken. Table 4 Trigeminal nerve deterioration defined as any transient or Contrary to what has previously been reported in some permanent impairment of trigeminal nerve function, either novel or single-center comparative studies [11, 26, 32], an increased worsening of preexisting symptoms risk of facial and trigeminal nerve deterioration was found in Author (year) Trigeminal nerve deterioration the included FRST studies compared to studies on SRS (Tables 3 and 4). For the purpose of this review, all reported SRS FSRT symptoms of nerve deterioration—mild and transient as well as permanent—were included in the analysis. Unger et al. [52]3/60 Iwai et al. [22]2/52 Hempel et al. [19]7/121 Liu et al. [29]5/74 Conclusion Chopra et al. [10]8/216 We identified several studies reporting the long-term tumor con- Fukuoka et al. [15]7/159 trol rate after SRS, while only two studies reported on long-term Roos et al. [48]15/102 tumor control after FSRT could be identified, engendering a more Sun et al. [50]44/190 robust support for favorable long-term tumor control with SRS. Yomo et al. [56]2/154 The risk for facial and trigeminal nerve deterioration was less for Hasegawa et al. [16, 17]3/440 patients treated in the SRS series compared to VS patients receiv- Boari et al. [6]26/379 ing FSRT, while the chance of preserved hearing showed no Wangerid et al. [53]3/128 difference between the two treatment groups. To establish guide- Aoyama et al. [2] 23/201 lines for radiotherapeutic treatment in vestibular schwannomas, a Litre et al. [28]7/155 RCT or a prospective controlled study comparing SRS and FSRT Total 125/2075 (6.0%) 30/356 (8.4%) would be needed. While awaiting results from such a study, this 1020 Acta Neurochir (2017) 159:1013–1021 series of unilateral vestibular nerve schwannoma surgical patients review reveals a need for FSRTcase series with larger cohorts and (acoustic neuroma). Surg Neurol 39:485–493 longer follow-up tim to obtain more solid data on long-term tumor 9. Chan AW, Black P, Ojemann RG, Barker FG 2nd, Kooy HM, Lopes control for this treatment modality. VV, McKenna MJ, Shrieve DC, Martuza RL, Loeffler JS (2005) Stereotactic radiotherapy for vestibular schwannomas: favorable out- come with minimal toxicity. Neurosurgery 57:60–70 discussion 60-70 Acknowledgements We express our gratitude to Eva Fjällgren at the Karolinska University Hospital library for extensive help with the sys- 10. Chopra R, Kondziolka D, Niranjan A, Lunsford LD, Flickinger JC tematic literature search. (2007) Long-term follow-up of acoustic schwannoma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys 68:845–851 Compliance with ethical standards 11. Choy W, Spasic M, Pezeshkian P, Fong BM, Nagasawa DT, Trang A, Mathur I, De Salles A, Gorgulho A, Selch M, Gopen QS, Yang I Funding No funding was received for this research. (2013) Outcomes of stereotactic radiosurgery and stereotactic radio- therapy for the treatment of vestibular schwannoma. Neurosurgery Conflict of interest None. 60:120–125 12. Chung HT, Ma R, Toyota B, Clark B, Robar J, McKenzie M (2004) Ethical approval All procedures performed in studies involving hu- Audiologic and treatment outcomes after linear accelerator-based man participants were in accordance with the ethical standards of the stereotactic irradiation for acoustic neuroma. Int J Radiat Oncol institutional and/or national research committee and with the 1964 Biol Phys 59:1116–1121 Helsinki Declaration and its later amendments or comparable ethical 13. Combs SE, Welzel T, Kessel K, Habermehl D, Rieken S, Schramm O, standards. For this type of study formal consent is not required. 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Int J Radiat Oncol Biol Phys 59:928–942 surgical community to conduct multicenter comparative studies on VS. 42. Pollock BE, Lunsford LD, Kondziolka D, Flickinger JC, Bissonette Still, we owe this to our patients to provide them with the best treatment. DJ, Kelsey SF, Jannetta PJ (1995) Outcome analysis of acoustic Morten Lund-Johansen neuroma management: a comparison of microsurgery and stereo- tactic radiosurgery. Neurosurgery 36:215–224 discussion 224-219 Bergen, Norway.

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Published: Apr 13, 2017

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